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Substituted urea derivatives for treating cardiac diseases

A compound, chelate technology, applied in the field of pharmaceutical compositions, chemical entities for the treatment of heart disease, can solve problems such as unfavorable heart failure patients

Inactive Publication Date: 2007-09-12
CYTOKINETICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Current inotropic agents improve contractility by transiently increasing calcium via the adenylyl cyclase pathway or by inhibiting phosphodiesterase (PDE) to delay cAMP degradation, neither of which is beneficial in heart failure patients

Method used

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  • Substituted urea derivatives for treating cardiac diseases
  • Substituted urea derivatives for treating cardiac diseases
  • Substituted urea derivatives for treating cardiac diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0793] Example 1 Step 1

[0794]

[0795] To 1.0 equivalent of 1A anhydrous DMF (0.37M) solution, add Zn(CN) 2 (0.92 equivalent) and Pd (PPh 3 ) 4 (0.058 equivalent). Nitrogen was introduced into the reaction mixture and heated to 80°C overnight. Then add another 0.023 equivalent of Pd(PPh 3 ) 4 , And heat the reaction for another 6 hours. Then the reaction mixture was cooled to RT, diluted with 15 times volume of EtOAc (calculated as 1A), and the organic layer was washed 3 times with water and once with saline solution. The organic layer was dried over sodium sulfate, filtered and concentrated. Chromatographic purification on silica gel, with 10% Et 2 O / hexane was the eluent, and 1B (90%) was obtained as a solid.

[0796] Example 1 Step 2

[0797]

[0798] Less than 1.0 equivalent of 1B anhydrous Et 2 To the O (0.06M) solution, the diisobutyllithium aluminum hydride solution (1.1 equivalent, 1.0M solution in hexane) was added dropwise with a syringe. The resulting solution wa...

Embodiment 2

[0813] Example 2 Step 1

[0814]

[0815] To 1.0 equivalent of (4-fluoro-3-nitro-phenyl)-methanol (2A) in THF (about 1M 2A in THF) and (about 1.1 equivalents) of pyridine, about 1.1 equivalents of methanesulfonyl chloride was added. The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by flash chromatography on silica gel with 10%-50% EtOAc / hexane as the eluent to obtain 4-fluoro-3-nitro-benzyl methanesulfonate (2B) (57%).

[0816] Example 2 Step 2

[0817]

[0818] To 1.0 equivalent of 4-fluoro-3-nitro-benzyl methanesulfonic acid (2B) in DMF solution (about 0.6M 2B DMF solution), add about 1.05 equivalent of TEA and about 1.0 equivalent of tert-butyl piperazine-1-carboxylate ester. The mixture was stirred at room temperature for 30 minutes, diluted with EtOAc, and NH 4 Cl solution washing, drying (Na 2 SO 4 ),evaporation. Purified by flash chromatography on silica gel using 50% EtOAc / hexane as the eluent to obtain 4-(4-fluoro-3...

Embodiment 3

[0826] Example 3 Step 1

[0827]

[0828] At RT and N 2 Next, fill a round bottom flask with 1 equivalent of 3-chloro-2-fluoroaniline (3A), 1-methyl-2-pyrrolidone (about 1.5M 3A in NMP solution), 2.2 equivalents of sodium cyanide, and 1.35 equivalents of bromine Nickel(II). To N 2 At the same time, introduce additional NMP to reduce the concentration by half, and slowly warm the solution to 200±5℃, 2 After stirring for 4 days. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with 30 times the volume of tert-butyl methyl ether (MTBE) and filtered through Celite. Then wash the diatomaceous earth pad with 10 times the volume of MTBE. Organic matter is washed with 40 times volume of salt solution, 2×40 times volume of water and 40 times volume of salt solution. The combined organics were dried over sodium sulfate and concentrated to obtain a brown solid, which was vacuum dried at 40°C (~30 inches Hg) for 8 hours to obtain the compound of...

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PUM

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Abstract

Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.

Description

Technical field [0001] The present invention relates to substituted urea derivatives, in particular to chemical entities that selectively modulate myocardial fibrillary segments, and particularly to chemical entities, pharmaceutical compositions and methods for the treatment of heart diseases. Background technique [0002] "Sarcomere" is a beautifully organized cell structure that exists in the myocardium and skeletal muscle. It is composed of interlaced thick and thin filaments; it constitutes nearly 60% of the volume of heart cells. Thick muscle filaments are composed of "myosin", which is a protein responsible for converting chemical energy (ATP hydrolysis) into force and leading movement. Myosin and its functionally related cousins ​​are called motor proteins. The gracilis filaments are composed of protein complexes. One of the proteins is "actin" (filamentous polymer), which is the matrix that myosin pulls when force is generated. Binding to actin is a set of regulatory prot...

Claims

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Application Information

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IPC IPC(8): A61K31/40C07D401/02A61K31/42C07D401/04A61K31/44C07D401/12
CPCC07D239/42C07D295/26C07D213/75C07D513/04C07D271/113C07D401/10C07D401/12C07D261/14C07D491/04C07D263/48C07D211/56C07D487/04C07D417/10C07D417/00C07D417/12A61P43/00A61P9/00A61P9/04A61P9/10C07D401/04A61K31/42A61K31/44A61K31/17C07C275/32
Inventor 布拉德利·P.·摩根亚历克斯·穆奇卢普平埃丽卡·克里耐克托德·杼元戴维·摩根斯
Owner CYTOKINETICS INC
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